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The study of host susceptibility to infectious disease has shifted focus over the decades from one primarily centered on the organism and its characteristics to one centered on the host’s immune-defense mechanisms. Recent research has made clear, however, that there is a two-way relationship between host and invading microorganism in which factors released by the host in response to the microorganism alter infectivity and course of infection and in turn by which factors released by the microorganism alter host defense mechanisms to infection.The purpose of this volume is to highlight these sometimes symbiotic and sometimes detrimental bidirectional influences of host-on-pathogen and pathogen-on-host responses. In particular, this volume focuses on extraimmune host responses of the central nervous and neuroendocrine systems that are activated during stress and during infection.

Effective immunoprotection requires rapid recruitment of leukocytes into sites of surgery, wounding, infection, or vaccination. Immune cells circulate continuously on surveillance pathways that take them from the blood, through various organs, and back into the blood. This circulation is essential for the maintenance of an effective immune defense network ( Sprent and Tough, 1994 ).The numbers and proportions of leukocytes in the blood provide an important representation of the state of distribution of leukocytes in the body and of the state of activation of the immune system. A stress-induced change in leukocyte distribution within different body compartments is perhaps one of the most underappreciated effects of stress and stress hormones on the immune system.

The following chapter will review the evidence that exposure to the same intense acute stressor can produce dichotomous effects on immune function and host defense that are dependent on the type of immune response tested and will develop the hypothesis that a common neuroendocrine mechanism exists for both outcomes, that is, activation of the sympathetic nervous system (SNS). First, I will describe research supporting the hypothesis that excessive SNS activation can produce suppression of a measure of acquired immunity, the in vivo antibody response to a benign protein. Importantly, only “excessive” SNS activation can produce the immunosuppression. Frequently, stressor exposure stimulates the SNS response but does not excessively drive the response to produce a state of catecholamine depletion in innervated tissues.We predict in the absence of tissue norepinephrine (NE) depletion, stimulation of the SNS will not suppress acquired immunity. Second, I will review the research supporting the hypothesis that stress-induced activation of SNS facilitates innate immune host defense. The role of the SNS in stress-induced potentiation of innate immunity contrasts with that of SNS effects on acquired immunity in that it does not depend on excessive SNS drive or tissue catecholamine depletion. In our studies, innate immune function was assessed by measuring the host’s initial response to an in vivo bacterial challenge that depends on innate and not acquired immune cells (Campisi et al ., 2005).

Death from anthrax has been reported to occur from systemic shock. The lethal toxin (LeTx) is the major effector of anthrax mortality. Although the mechanism of entry of this toxin into cells is well understood, its actions once inside the cell are not as well understood. LeTx is known to cleave and inactivate mitogen activated protein kinase kinases (MAPKKs). We have recently shown that LeTx represses the glucocorticoid receptor both in vitro and in vivo . This repression is partial and specific, showing some receptor specificity and some promoter specificity.This toxin does not affect glucocorticoid receptor (GR) ligand binding or DNA binding in an in vitro electrophoretic mobility shift assay using a DNA probe. However, in chromatin immunoprecipitation assays, LeTx prevents GR binding to chromatin. We have suggested that LeTx may function by removing/inactivating one or more of the many cofactors and/or accessory proteins involved in nuclear hormone receptor signaling. Although the precise involvement of this nuclear hormone receptor repression in LeTx toxicity is unknown, examples of blunted hypothalamic-pituitary-adrenal (HPA) axis and glucocorticoid signaling in numerous autoimmune/inflammatory diseases suggest that such repression of critically important receptors could have deleterious effects on health. In addition, removal of endogenous glucocorticoids and treatment with glucocorticoids (in LT-resistant mice) increases susceptibility to LeTx, suggesting that a precise balance of glucocorticoid levels is required for LeTx survival.

The early hypothesis that the brain and immune system communicated with each other was first proposed from the results of a study on the effect of taste aversion conditioning of humoral immune responsiveness ( Ader and Cohen, 1975 ). Many studies have since confirmed the existence of such a bidirectional regulation [reviewed in ( Besedovsky and Del Rey, 1996 ; Ader, 2000 ; Kohm and Sanders, 2001 )] and provide plausible mechanisms by which the immune system alerts the brain that it is responding to an antigen, as well as mechanisms by which the brain regulates the level of immune cell activity that develops (Figure 5.1). Four key discoveries indicate that mechanisms exist by which the brain is able to communicate with cells of the peripheral immune system. First, primary and secondary lymphoid organs are innervated with sympathetic nerve fibers, and mechanisms exist by which signals are sent from the activated immune system to the brain. Second, the sympathetic neurotransmitter norepinephrine (NE) is released from nerve terminals residing within the parenchyma of lymphoid tissues after antigen or cytokine administration. Third, lymphoid cells, except for Th2 cells, express the α2-adrenergic receptor (β_2AR) that binds NE to transduce extracellular signals to the cell interior. And finally, NE regulates lymphocyte activity at the level of gene expression. Although NE appears to regulate immune system activity overall, we will focus this chapter to a discussion of the role NE plays in regulating CD4^+ T-cell and B-cell activity, with special emphasis placed on the role it plays in regulating the level of cytokine and antibody produced.

Trauma remains the major cause of deaths in the United States and in other developing countries. Moreover, a significant number of trauma victims who survive initial injury succumb subsequently because of sepsis and multiple organ failure ( Bone, 1992 ; Nathens and Marshall, 1996 ; Baue et al., 1998 ; Marshall, 1999 ; Angele et al., 2000 ; Baue, 2000 ; Choudhry et al., 2003 ).Thus, sepsis and organ dysfunction continue to be the major cause of morbidity and mortality in trauma patients. Although intensive investigations during the past three decades have helped identify some of the mechanisms responsible for sepsis and organ dysfunction, despite all these efforts the prognosis of trauma patients remains elusive. Furthermore, these studies suggest that the postinjury pathogenesis is complex and is influenced by multiple factors.Among these, gender is suspected to be a major factor that plays a significant role in shaping the host response to injury ( Schroder et al., 1998 ; Angele et al., 2000 ; Schroder et al., 2000 ; Croce et al., 2002 ; Yokoyama et al., 2002 ; Chaudry et al., 2003 ; George et al., 2003b ; Choudhry et al., 2004 ). The primary aim of this article is to present a comprehensive summary of the studies dealing with the role of gender in response to trauma as well as to discuss potential targets that can be used to modulate endogenous levels of sex hormones to improve organ functions after experimental trauma.

There is extensive anecdotal evidence supporting an association between psychological stress and one’s susceptibility to a variety of infectious pathogens. These pathogens include a number of viruses with significant short- and long-term health consequences. Infections with one such virus, herpes simplex virus (HSV), have long been recognized to be linked to a variety of life stressors. These HSV infections, both primary and recurrent, have been thought to be, in part, a function of a decreased immune surveillance and a suppression of antiviral immune defense mechanisms. Such stress-induced alterations in immune capacity may be mediated by one or more products of the nervous and endocrine systems.A number of human and animal studies have provided data to support this hypothesis and represent a subset of a larger group of studies that have established a solid link among psychological stress, immune function, and diseases caused by pathogenic microorganisms (reviewed in Moynihan and Ader, 1996 ; Sheridan et al., 1998 ; Bonneau et al., 2001 ; Bailey et al., 2003 ; Moynihan and Stevens, 2004). Recent advances in experimental immunology have broadened our knowledge of immunological processes that, in turn, have facilitated the design of studies to better examine the interactions among the nervous, endocrine, and immune systems at both the cellular and molecular levels. The information provided in this chapter will review some of the studies that have established a link between stress and HSV, and the impact of this link on human health will be discussed.

If you believe what you read in the newspapers, the world is poised for a pandemic. The scourge is likely to be infection with the influenza A virus. Although there may be some doubt concerning these cataclysmic predictions, they are based on solid epidemiological and historical data. It is well documented that during the past several centuries, an influenza virus pandemic has raced through the human population every 20–40 years or so. In 1918–1919, a pandemic due to influenza virus infected one out of every five humans. This “Spanish Flu,” which was also known as “La Grippe,” is estimated to have killed more than 30 million people in less than 2 years ( Mills et al., 2004 ). To put this in perspective, this influenza pandemic killed one out of every four soldiers that died during World War I ( Oxford et al., 2005 ). Luckily, there has not been a repeat of the 1918–1919 pandemic. However, recent events such as the emergence of the avian influenza that is currently causing mortality in Asia may signal the evolution of a new, highly virulent influenza virus that might cause a serious worldwide influenza epidemic.

During the past decade, our laboratory has carried out a series of studies analyzing the effects of autonomic nervous system (ANS) activity on HIV- 1 pathogenesis ( Cole et al., 1998 ). These studies were motivated by natural history studies showing accelerated HIV disease progression in gay men who had socially inhibited personality characteristics ( Cole et al., 1996, 2003 ). Previous developmental studies have suggested that socially inhibited individuals show elevated levels of ANS activity ( Block, 1957 ; Buck et al., 1974 ; Cole et al., 1999b ; Miller et al., 1999 ), providing a potential neurobiological basis for differential HIV disease progression. In a subsequent cohort study of 54 HIV-positive gay men with early- to mid-stage infection (no AIDS, and CD4^+ T cell levels > 200/mm3), we found that socially inhibited individuals did indeed show elevated levels of ANS activity. ANS activity was measured across a range of end-organ responses including palmar skin conductance, blood pressure, heart rate interbeat interval, finger pulse amplitude, and peripheral pulse transit time (time from heart beat to subsequent finger pulse peak) (Fig. 9.1). Baseline autonomic activity and reactivity to a series of physical, psychological, and social stimuli was found to be stable over time. Individuals showing constitutively high levels of ANS activity also showed elevated plasma viral load (Fig. 9.1) and impaired suppression of viremia and CD4^+ T-lymphocyte recovery after the onset of combination antiretroviral therapy ( Cole et al., 2001 , 2003 ).

Physical and psychosocial stressors have been shown to compromise immune function ( Ader et al., 1991 ; Kielcolt-Glaser and Glaser, 1995 ). The immune suppressive effects of stress may be more pronounced in individuals that already have limited immune competence, such as infants, individuals with a predisposition to autoimmune disease, and the elderly ( Kielcolt-Glaser and Glaser, 1995 ). An individual’s response to a stressor is manifested in physiological, hormonal, behavioral, and immunological changes. These stress-induced responses are initiated by the hypothalamus and translated into action by the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. Products from these two systems (e.g., corticoid hormones and catecholamines) can directly modulate the activity of various immune effector cells ( Ader et al., 1991 ).